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What Are the Main Characteristics of AD?: Amyloid Plaques

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By 1999 Progress Report by the NIA/NIH • • December 13, 1999

In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. They consist of largely insoluble deposits of beta-amyloid--a protein fragment snipped from a larger protein called amyloid precursor protein (APP)--intermingled with portions of neurons and with non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances that cause inflammation) and astrocytes (cells that serve to support neurons). Researchers still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process. Certainly, changes in the APP protein can cause AD, as shown in the inherited form of AD caused by mutations in the APP gene (see p. 13 for more on inherited AD).

APP is one of many proteins that are associated with cell membranes. The cell membrane encloses the cell and acts as a barrier that selects which substances can go in and out of the cell. After it is made, APP becomes embedded in the nerve cell's membrane, partly inside and partly outside the cell, like a needle poking through a piece of fabric. Recent studies using transgenic (genetically engineered) mice show that APP appears to play an important role in the growth and survival of neurons. For example, certain forms and amounts of APP may protect neurons against both short- and long-term damage. In test tube studies, scientists have found that APP may play a role in making damaged neurons better able to repair themselves and help parts of neurons grow after brain injury. While APP is embedded in the cell membrane, proteases (a particular kind of enzyme, or substance, that speeds up or causes chemical reactions in the body--in this case, cutting proteins into fragments) act on particular sites in APP, cleaving it into protein fragments. One protease helps cleave APP to form beta-amyloid, and another protease cleaves APP in the middle of the amyloid fragment so that beta-amyloid cannot be formed. The beta-amyloid formed is of two different lengths, a shorter beta-amyloid that is more soluble and aggregates slowly, and a slightly longer, "sticky" beta-amyloid that rapidly forms insoluble clumps. While beta-amyloid is being formed, scientists do not yet know exactly how it moves through or around nerve cells. In the final stages of this process, the "sticky" beta-amyloid aggregates into long filaments outside the cell and, along with fragments of dead and dying neurons and the microglia and astrocytes, forms the plaques that are characteristic of AD in brain tissue.

National Institutes of Health
National Institute on Aging

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